E EDITORIAL

Botulinum Toxin Type B for Chronic Pain: Panacea or Snake Oil? The Need for More and Better Preclinical Studies Steven P. Cohen, MD

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hronic pain, which includes spinal pain, neuropathic pain, headaches, and musculoskeletal pain, is by far the leading cause of disability in the world.1 Largescale studies, including a recent Institute of Medicine report on the burden of chronic pain in the United States, cite prevalence rates ranging between 25% and 33%.2,3 Among patients with chronic pain, approximately 20% to 25% is characterized as predominantly neuropathic in origin.4–6 These sobering statistics augur strongly for the need for new tools to try to stem the growing burden of neuropathic pain. Botulinum toxin (BoNT) is a neurotoxin produced by the bacterium Clostridium botulinum that induces muscle paraly­ sis—a disease known as “botulism” in infected, untreated individuals—by interfering with the release of acetylcholine at the neuromuscular junction. The compound is somewhat unusual as an analgesic in that clinical studies touting benefit in pain conditions predated animal studies.7 Although its use in pain medicine was initially limited to conditions characterized by muscle pathology, clinical trials have subsequently demonstrated benefit for a wide array of pain conditions, including neuropathic pain, headaches, plantar fasciitis, interstitial cystitis, and musculoskeletal disorders.8 One caveat that should be heeded when considering versatile, multipurpose analgesic medications is that because most pain conditions are characterized by different mechanisms, treatments that are deemed to be effective for multifarious pain conditions (i.e., work at multiple levels or via different mechanisms) tend to be associated with manifold and/or significant side effects. For BoNT, these include but are not limited to local or even generalized muscle weakness. However, even when clinical evidence exists to support a given treatment, preclinical From the Department of Pain Medicine, Johns Hopkins Hospital, Baltimore, Maryland. Accepted for publication February 5, 2015. Funding: Funded in part by a Congressional Grant from the Center for Rehabilitation Sciences Research, Bethesda, MD. The author declares no conflicts of interest. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Reprints will not be available from the author. Address correspondence to Steven P. Cohen, MD, Department of Pain Medicine, Johns Hopkins Hospital, 550 North Broadway, Suite 301, Baltimore, MD 21029. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000727

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studies are important to refine patient selection and indications, improve delivery systems, and enhance safety. In an elegant study in this issue of the journal, Park et al.9 evaluated the efficacy of BoNT type B (BoNT-B) in 2 models of neuropathic pain in a randomized, evaluator-blinded, placebocontrolled study. In one group of mice, a mononeuropathy was induced by tight ligation of the L5 nerve root. In another group of mice, a polyneuropathy was induced by the injection of intraperitoneal cisplatin every other day for 2 weeks. In the control animals, the L5 nerve root was surgically exposed but not ligated (mononeuropathy control), whereas in the polyneuropathy control group, saline was injected intraperitoneally. To test efficacy in the mononeuropathy group, the animals received either an intraplantar injection of 0.3 to 1.5 units of BoNT-B or saline into their ipsilateral hindpaw 14 days after nerve ligation, whereas those in the polyneuropathy group received 0.1 to 0.5 units of BoNT-B or saline injected intrathecally 15 days after the start of the cisplatin injection series. To augment the robustness of the results, 2 additional controls were used in the mononeuropathy group. In one group, BoNT was injected into the contralateral paw, whereas for the other control BoNT-B treated with dithiothreitol was administered, which functions to cleave the heavy chain from the light chain, thereby rendering the toxin inactive. Outcome measures, including mechanical allodynia, motor function, and activation transcription factor-3 levels, whose expression increases in dorsal root ganglia after nerve injury, were recorded through 4 weeks after treatment. The evaluation of 2 different routes of administration using a range of dosages for 2 different types of neuropathic pain with multiple control groups provides us with the ability to determine both the site(s) of action for BoNT toxin and assess dose responsiveness. The authors found that intraplantar BoNT resulted in a mostly ipsilateral, dose-dependent reversal of allodynia (at higher dosages a modest contralateral effect was noted that was attributed to systemic redistribution), whereas intrathecal administration was associated with bilateral reversal. In mice treated with saline or pretreated with dithiothreitol, the antiallodynic effects of BoNT-B were blocked. The antiallodynic effects of lasted 17 and 21 days in the intrathecal and intraplantar BoNT groups, respectively, which is shorter than the effects observed in clinical studies. In both the intraplantar and intrathecal treatment groups, body weights were significantly lower than in control groups, although this was attributed to lower pretreatment body July 2015 • Volume 121 • Number 1

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Botox for Neuropathic Pain

weights in mice administered intrathecal BoNT-B, and post hoc analysis was only significant at day 7 in the intraplantar-injected animals. Increased expression of activation transcription factor-3 in the dorsal root ganglia was reduced with intrathecal but not intraplantar delivery. What can we learn from these findings? Collectively, these findings suggest both a peripheral and central effect for BoNT, which may have implications for improved delivery systems and indications (e.g., epidural administration for sciatica, or another intrathecally administered analgesic “toxin” akin to ziconotide for neuropathic pain). In humans, locally injected BoNT has not been found to have a beneficial effect on acute pain thresholds.10,11 In clinical trials evaluating its effect on symptoms of neuropathic pain such as allodynia and hyperalgesia,12,13 the results have been decidedly mixed, which is in contrast to this and other animal studies which generally show benefit.14,15 But, they should also serve as a cautionary measure for overzealous or inappropriate use, as muscle paralysis ensued when higher intraplantar doses (≥2 units) were injected. Although the implications of these findings most definitely improve our understanding of the mechanisms of action of BoNT and may someday broaden the indications and increase safety, the results need to be placed in context. First, animal studies for the most part have received a “free pass” on methodological quality indicators that are now routinely expected in clinical trials. In a systematic review and meta-analysis evaluating the methodological quality of animal models of bone cancer pain, the authors found that none reported sample size calculation, 31% had blinded assessment of outcome, and only 11% reported random allocation to treatment group (animal studies are usually not randomized because it is assumed that since in-bred animals are physically indistinguishable, they are also behaviorally identical, which is not always the case).16 In this study, randomization was not noted, the number of animals per treatment group was small (range, 4–8), no power analysis was performed, and although evaluators were blinded, those performing the treatments were not. Other drawbacks that have limited the generalizability of animal studies to humans (>90% of drugs that pass animal tests fail in clinical trials) include that animal studies typically measure evoked but not spontaneous pain; most animal models fail to consider the affective-motivational component of chronic pain; the outcomes assessed are generally short term; important secondary outcome measures such as sleep, psychosocial function, and functional capacity are not measured; and that animal models actually measure objective behavioral consequences of nociception (e.g., paw withdrawal) rather than pain itself, which is inherently subjective. The failure to translate success in animal models to measurable benefit in humans raises some important questions, such as: “What does pain mean to a rodent?” and “Do we need to rethink the nocifensive behavioral testing models that pervade preclinical studies and consider operant conditioning models that try to account for pain-affect?”17 The pervasive shortcomings in preclinical research result in billions of dollars and tens of thousands of hours wasted (not to mention the (dis)stress the animals experience) on endeavors that will never reach fruition. So whereas this technically creative study holds the potential to provide meaningful benefit down

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the road to humans experiencing neuropathic pain, the results must be viewed with caution. E DISCLOSURES

Name: Steven P. Cohen, MD. Contribution: This author wrote the manuscript. Attestation: Steven P. Cohen approved the final manuscript. This manuscript was handled by: Jianren Mao, MD, PhD. REFERENCES 1. US Burden of Disease Collaborators. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA 2013;310:591–608 2. Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. Washington, DC: The National Academies Press, 2011. Available at: http://books.nap.edu/openbook. php?record_id=13172&page=1. Accessed August 16, 2013 3. Leadley RM, Armstrong N, Lee YC, Allen A, Kleijnen J. Chronic diseases in the European Union: the prevalence and health cost implications of chronic pain. J Pain Palliat Care Pharmacother 2012;26:310–25 4. Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ 2014;348:f7656 5. Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 2008;136:380–7 6. de Moraes Vieira EB, Garcia JB, da Silva AA, Mualem Araújo RL, Jansen RC. Prevalence, characteristics, and factors associated with chronic pain with and without neuropathic characteristics in São Luís, Brazil. J Pain Symptom Manage 2012;44:239–51 7. Tsui JK, Eisen A, Stoessl AJ, Calne S, Calne DB. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;2:245–7 8. Guo BL, Zheng CX, Sui BD, Li YQ, Wang YY, Yang YL. A closer look to botulinum neurotoxin type A-induced analgesia. Toxicon 2013;71:134–9 9. Park HJ, Marino MJ, Rondon ES, Xu Q, Yaksh TL. The effects of intraplantar and intrathecal botulinum toxin type B on tactile allodynia in mono and polyneuropathy in the mouse. Anesth Analg 2015;121:229–38 10. Sycha T, Samal D, Chizh B, Lehr S, Gustorff B, Schnider P, Auff E. A lack of antinociceptive or antiinflammatory effect of botulinum toxin A in an inflammatory human pain model. Anesth Analg 2006;102:509–16 11. Schulte-Mattler WJ, Opatz O, Blersch W, May A, Bigalke H, Wohlfahrt K. Botulinum toxin A does not alter capsaicin-induced pain perception in human skin. J Neurol Sci 2007;260:38–42 12. Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 2008;64:274–83 13. Safarpour D, Salardini A, Richardson D, Jabbari B. Botulinum toxin A for treatment of allodynia of complex regional pain syndrome: a pilot study. Pain Med 2010;11:1411–4 14. Marinelli S, Luvisetto S, Cobianchi S, Makuch W, Obara I, Mezzaroma E, Caruso M, Straface E, Przewlocka B, Pavone F. Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models. Neuroscience 2010;171:316–28 15. Mika J, Rojewska E, Makuch W, Korostynski M, Luvisetto S, Marinelli S, Pavone F, Przewlocka B. The effect of botulinum neurotoxin A on sciatic nerve injury-induced neuroimmunological changes in rat dorsal root ganglia and spinal cord. Neuroscience 2011;175:358–66 16. Currie GL, Delaney A, Bennett MI, Dickenson AH, Egan KJ, Vesterinen HM, Sena ES, Macleod MR, Colvin LA, Fallon MT. Animal models of bone cancer pain: systematic review and meta-analyses. Pain 2013;154:917–26 17. Li JX. The application of conditioning paradigms in the measurement of pain. Eur J Pharmacol 2013;716:158–68

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Botulinum toxin type B for chronic pain: panacea or snake oil? The need for more and better preclinical studies.

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